Is allergen absorption a key determinant of severity in food-induced reactions?
Authors: Paul J. Turner
Journal: Journal of Allergy and Clinical Immunology (2022)

Gertie et al1Gertie J.A. Zhang B. Liu E.G. Hoyt L.R. Yin X. Xu L. et al.Oral anaphylaxis to peanut in a mouse model is associated with gut permeability but not with Tlr4 or Dock8 mutations.J Allergy Clin Immunol. 2022; 149: 262-274Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar report a well-conducted set of experiments in a murine anaphylaxis model of orally administered peanut, in which they demonstrate an association between enhanced gut permeability to oral antigens and susceptibility to anaphylaxis. The authors suggest that physical disruption of gut barrier integrity could lead to an increased susceptibility to oral anaphylaxis in humans. The severity of food-induced allergic reactions is also influenced by the presence (or absence) of cofactors, including some medications and exercise. Of note, nonsteroidal anti-inflammatory drugs such as aspirin and exercise may influence severity through an impact on allergen absorption. Although the gastrointestinal epithelial barrier function can be impaired in food allergy, consistent evidence is lacking in humans, and maintaining an allergen-free diet appears to restore gut barrier function,2Verhoeckx K. Bøgh K.L. Dupont D. Egger L. Gadermaier G. Larré C. et al.The relevance of a digestibility evaluation in the allergenicity risk assessment of novel proteins. Opinion of a joint initiative of COST action ImpARAS and COST action INFOGEST.Food Chem Toxicol. 2019; 129: 405-423Crossref PubMed Scopus (35) Google Scholar at least in non–IgE-mediated food allergy.3Heyman M. Grasset E. Ducroc R. Desjeux J.F. Antigen absorption by the jejunal epithelium of children with cow’s milk allergy.Pediatr Res. 1988; 24: 197-202Crossref PubMed Scopus (119) Google Scholar In wheat-dependent, exercise-induced anaphylaxis, a plausible mechanism of action is an exercise-related increase in gut permeability and/or allergen absorption, leading to more severe clinical reactions.4Matsuo H. Morimoto K. Akaki T. Kaneko S. Kusatake K. Kuroda T. et al.Exercise and aspirin increase levels of circulating gliadin peptides in patients with wheat-dependent exercise-induced anaphylaxis.Clin Exp Allergy. 2005; 35: 461-466Crossref PubMed Scopus (217) Google Scholar The detection of food proteins in serum following consumption is challenging.5Bernard H. Turner P.J. Ah-Leung S. Ruiz-Garcia M. Clare Mills E.N. Adel-Patient K. Circulating Ara h 6 as a marker of peanut protein absorption in tolerant and allergic humans following ingestion of peanut-containing foods.Clin Exp Allergy. 2020; 50: 1093-1102PubMed Google Scholar Nonetheless, we have previously reported that absorption kinetics for peanut are significantly different in peanut-allergic volunteers compared with nonallergic controls (Fig 1). For any given dose of peanut ingestion, there is higher Ara h 6 detection in serum samples from peanut-allergic individuals compared with controls, and peanut can be detected in the blood after much lower levels of ingestion, compared with controls.5Bernard H. Turner P.J. Ah-Leung S. Ruiz-Garcia M. Clare Mills E.N. Adel-Patient K. Circulating Ara h 6 as a marker of peanut protein absorption in tolerant and allergic humans following ingestion of peanut-containing foods.Clin Exp Allergy. 2020; 50: 1093-1102PubMed Google Scholar Taken together with the data reported by Gertie et al, in-human data thus suggest that although chronic allergen exposure can impair gut barrier function (and contribute to the development of sensitization), this seems to be reversible with dietary avoidance.2Verhoeckx K. Bøgh K.L. Dupont D. Egger L. Gadermaier G. Larré C. et al.The relevance of a digestibility evaluation in the allergenicity risk assessment of novel proteins. Opinion of a joint initiative of COST action ImpARAS and COST action INFOGEST.Food Chem Toxicol. 2019; 129: 405-423Crossref PubMed Scopus (35) Google Scholar,3Heyman M. Grasset E. Ducroc R. Desjeux J.F. Antigen absorption by the jejunal epithelium of children with cow’s milk allergy.Pediatr Res. 1988; 24: 197-202Crossref PubMed Scopus (119) Google Scholar Acute allergen exposure does result in a change in the kinetics of gastrointestinal allergen absorption; however, other mechanisms—distinct from defects in gut permeability—may also contribute to severity outcomes in food allergy, including IgE-dependent facilitated uptake of antigens.2Verhoeckx K. Bøgh K.L. Dupont D. Egger L. Gadermaier G. Larré C. et al.The relevance of a digestibility evaluation in the allergenicity risk assessment of novel proteins. Opinion of a joint initiative of COST action ImpARAS and COST action INFOGEST.Food Chem Toxicol. 2019; 129: 405-423Crossref PubMed Scopus (35) Google Scholar,5Bernard H. Turner P.J. Ah-Leung S. Ruiz-Garcia M. Clare Mills E.N. Adel-Patient K. Circulating Ara h 6 as a marker of peanut protein absorption in tolerant and allergic humans following ingestion of peanut-containing foods.Clin Exp Allergy. 2020; 50: 1093-1102PubMed Google Scholar Individuals with a history of truly severe, life-threatening anaphylaxis may have altered absorption kinetics for their trigger food antigen(s), resulting in greater systemic allergen absorption and a more profound immune response. Research is needed to evaluate this possibility, and whether interventions that reduce systemic absorption of specific food allergens from the gut may be a potential therapeutic strategy for those most at risk of severe anaphylaxis. Oral anaphylaxis to peanut in a mouse model is associated with gut permeability but not with Tlr4 or Dock8 mutationsJournal of Allergy and Clinical ImmunologyVol. 149Issue 1PreviewThe etiology of food allergy is poorly understood; mouse models are powerful systems to discover immunologic pathways driving allergic disease. C3H/HeJ mice are a widely used model for the study of peanut allergy because, unlike C57BL/6 or BALB/c mice, they are highly susceptible to oral anaphylaxis. However, the immunologic mechanism of this strain’s susceptibility is not known. Full-Text PDF ReplyJournal of Allergy and Clinical ImmunologyVol. 150Issue 2PreviewIn his correspondence, Turner1 argues that factors other than increased intestinal permeability contribute to heightened food allergen absorption in humans prone to severe allergic reactions and anaphylaxis. He notes that there is a lack of evidence supporting the role of heightened intestinal permeability in mediating symptomatic food allergy in humans, and that gut-barrier dysfunction may be a result of allergic inflammation, rather than a cause. These critiques highlight both the challenges of studying food allergy in humans and the need to understand differences that may exist in food allergy pathogenesis between humans and mice. Full-Text PDF